|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-08-2543.
NEOPLASIA
From the Jerome Lipper Multiple Myeloma Center,
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
We have recently shown that proteasome inhibitor PS-341
induces apoptosis in drug-resistant multiple myeloma (MM) cells,
inhibits binding of MM cells in the bone marrow microenvironment, and
inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and
prolongs survival in a SCID mouse model. Importantly, PS-341 has
achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341
mediates anti-MM activity by inducing p53 and MDM2 protein expression;
inducing the phosphorylation (Ser15) of p53 protein; activating
c-Jun NH2-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2.
Inhibition of JNK activity abrogates PS-341-induced MM cell death.
These studies identify molecular targets of PS-341 and provide the
rationale for the development of second-generation, more targeted therapies.
(Blood. 2003;101:1530-1534) The ubiquitin-proteasome pathway (UPP) is a
proteolytic system in the cytosol and nucleus that regulates cyclins
and cyclin-dependent kinase inhibitor cell-cycle regulatory proteins
and thereby regulates cell-cycle progression.1 UPP also
has a critical role in the selective removal of mutant, damaged, and
misfolded proteins. Proteasome inhibitors have recently demonstrated
promise as potential novel anticancer therapies2 because
they induce the apoptosis of tumor cells in vitro, despite the
accumulation of p21 and p273,4 and irrespective of the p53
wild-type or mutant status5,6 in tumor cells.
Specifically, PS-341 (pyrazylcarbonyl-Phe-Leu-boronate) is
representative of a class of peptide boronate proteasome inhibitors that inhibit 26S proteasome activity.1 This agent induces
marked in vivo antitumor activity against human prostate
cancer,2,7 Burkitt lymphoma in a murine
model,8 and adult T-cell leukemia9; produces Multiple myeloma (MM) is a hematologic malignancy that affected
14 000 new patients in the United States in 2000,12 and it remains incurable with conventional therapies. Novel biologically based therapies are, therefore, urgently needed. We have previously demonstrated that PS-341 directly induces apoptosis by the activation of caspase-3 and without the associated alteration of Bax or Bcl-2 protein expression, even in MM cell lines and patient MM cells that are
resistant to conventional therapies. PS-341 also overcomes the
antiapoptotic effects of interleukin-6 (IL-6) or adherence to bone
marrow stromal cells (BMSCs).4 In vivo PS-341 inhibits human MM cell growth and associated angiogenesis and prolongs survival
in a murine SCID mouse model. Most important, PS-341 has achieved
responses, even complete responses, in a phase 2 clinical trial
treating patients with relapsed MM refractory to conventional
therapies, and it has an acceptable toxicity profile.13 This drug, therefore, represents a new treatment paradigm targeting not
only the tumor cell but also the MM cell-host interaction and the bone
marrow (BM) milieu to overcome drug resistance and improve patient outcome.
Both proapoptotic and antiapoptotic proteins are substrates of
UPP,1 and the molecular mechanisms whereby PS-341 mediates its anti-MM activity are not yet defined. In this study, we demonstrate that PS-341 induces p53 and MDM2 protein expression; induces
phosphorylation (Ser15) of p53 protein; and activates c-Jun
NH2-terminal kinase (JNK), which in turn activates
caspase-8 and caspase-3. Activated caspase-3, in turn, cleaves DNA
protein kinase catalytic subunit (DNA-PKcs), ATM, and MDM2; conversely,
caspase inhibitors Z-VAD-FMK and Z-IETD-FMK abrogate these effects.
Furthermore, the inhibition of JNK activity by SP600125 reduces
PS-341-induced MM cell death. Our results demonstrate that PS-341
induces caspase activation, inhibits DNA repair, and activates p53 by
phosphorylation and degradation of MDM2. Given the early clinical
promise and favorable toxicity profile of PS-341 in patients with
relapsed refractory MM, these studies provide the framework for further
clinical evaluation of PS-341, alone and coupled with conventional or
other novel therapies, to improve patient outcome in MM.
MM-derived cell lines and patient MM cells
Reagents
Growth inhibition assay MM.1S cells were cultured for 24 hours with 6-25 nM PS-341 in the presence (5-10 µM) or absence of SP600125. The inhibitory effect of PS-341 on MM cell growth in the presence or absence of SP600125 was assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT; Chemicon International, Temecula, CA) dye absorbance, as previously described.14,17Preparation of biotinylated probes and hybridization on microarrays MM.1S cells were incubated with 20 nM PS-341 for 0.5, 1, 3, and 6 hours in the presence of 5% FBS. mRNA expression profiling was analyzed using Affymetrix huGene FL arrays (Santa Clara, CA) containing 12 626 genes, as previously described.18Immunoblotting MM cell lines and patient MM cells cultured with PS-341 were lysed, and protein lysates (50 µg) were subjected to Western blotting, as in prior studies.11,17 Nuclear extracts were prepared using the Nuclear Extract Kit (Activemotif, Carlsbad, CA), according to the manufacturer's instructions. Antibodies used for immunoblotting included anti-phospho-p53 (Ser6, Ser9, Ser15, Ser20, Ser37, Ser46, Ser392), p53, phospho-SEK1, phospho-SAPK, phospho-c-Jun, phospho-ATF-2, phospho-Bcl-2, and caspase-8 (Cell Signaling, Beverly, MA); anti-MDM2, -JNK1, -DNA-PKcs, -Bcl-2, -Bcl-XL, - -tubulin, and
-nucleolin (Santa Cruz Biotechnology, Santa Cruz, CA); anti-ATM
(Oncogene Research Products, Boston, MA); and anti-caspase-3 (BD
PharMingen). For immunoprecipitation, whole-cell lysates were incubated
with anti-p53 and MDM2 overnight at 4°C and then incubated with
protein A/G PLUS-Agarose (Santa Cruz Biotechnology) for 4 hours at
4°C as in our prior study.14,19
Statistical analysis Statistical significance of differences observed in drug-treated versus control cultures was determined using the Wilcoxon signed-rank test. The minimal level of significance was P < .05.
PS-341 up-regulates expression of p53 and MDM2 proteins and induces phosphorylation (Ser15) of p53 Because p53 is a substrate of UPP, we first examined the effect of PS-341 on p53 protein expression in MM.1S cells. MM.1S cells were treated with PS-341 (20 nM) for up to 16 hours in the presence of 5% FBS. As expected, p53 protein expression was transiently up-regulated after PS-341 treatment in MM.1S cells, with peak expression at 8 hours (Figure 1A). PS-341 also induces transient p53 phosphorylation on Ser15 without the phosphorylation of Ser6, Ser9, Ser20, Ser37, Ser46, or Ser392 residues (data not shown), in the same pattern as p53 protein expression. MDM2 protein is also transiently up-regulated after PS-341 treatment, with peak protein expression observed at 6 hours. We next examined the dose-dependent effect of PS-341 on phosphorylation and protein expression of these proteins. Phosphorylation (Ser15) and protein expression of p53 are up-regulated in a dose-dependent fashion; in contrast, MDM2 expression was decreased only after high-dose PS-341 treatment (Figure 1B). To assess the effect of PS-341 in patient MM cells, we next purified the MM cells from patient bone marrow aspirates. As can be seen in Figure 1C, PS-341 treatment (20 nM, 8 hours) induces the phosphorylation of p53 (Ser15) and up-regulates p53 and MDM2 protein expression in patient MM cells. Because DNA damage induces p53 phosphorylation,20,21 these results suggest that PS-341 induces DNA damage in MM cell lines and patient MM cells. We further examined the distribution and interaction of p-p53, p53, and MDM2 proteins. As expected, most p-p53 is present in the nucleus, and PS-341 triggered increased protein expression associated with the nuclear translocation of p-p53. In contrast, cytoplasmic p53 is in its nonphosphorylated form (Figure 1D). We also examined the association of p53 and MDM2 protein using coimmunoprecipitation with anti-p53 and MDM2 antibodies, and we demonstrated that PS-341 induces coimmunoprecipitation of p53 with MDM2 protein in a time-dependent fashion (Figure 1E). PS-341-induced interaction of p53 and MDM2 occurs earlier than the induction of p53 protein.
PS-341 induces c-Jun NH2-terminal kinase activation We next examined whether PS-341 induces a stress response in MM.1S cells. PS-341 induces the phosphorylation of JNK, and upstream (SEK-1) and downstream (c-Jun and ATF-2) proteins, in a time- (Figure 2A) and dose- (Figure 2B) dependent fashion. PS-341 similarly induces the phosphorylation of JNK in U266 and RPMI 8226 MM cell lines (Figure 2C). As we have done in dexamethasone-treated MM.1S cells,18 we next performed gene microarray profile analysis in MM.1S cells before and after PS-341 treatment. As seen in Figure 2D, PS-341 induces a significant (2.5- to 72-fold) increase in heat shock protein (HSP) transcription in a time-dependent fashion. These results indicate that PS-341 induces a stress response in MM cell lines.
Inhibition of JNK activity reduces PS-341-induced cell death by inhibition of caspase-3 activation To examine whether the activation of JNK plays a role in mediating PS-341-induced apoptosis, we used JNK-specific inhibitor SP600125.15,16 In the presence of SP600125, the phosphorylation of JNK triggered by PS-341 is completely abrogated in a dose-dependent fashion (Figure 3A). Phosphorylation of c-Jun or ATF-2 is also blocked by SP600125 (data not shown). SP600125 does not block the phosphorylation of p53 or the induction of MDM2 by PS-341. We further examined whether the inhibition of JNK activity also inhibits caspase-3 cleavage. As seen in Figure 3B, SP600125 inhibits PS-341-induced caspase-3 cleavage, consistent with its inhibition of JNK phosphorylation. SP600125 in a dose-dependent fashion also significantly (P < .01) inhibits PS-341-induced cytotoxicity in MM.1S cells, assessed by MTT assay (Figure 3C). These results suggest that JNK plays a critical role in mediating PS-341-induced apoptosis through the activation of caspase-3.
PS-341 induces DNA-PKcs and ATM cleavage in MM Others have demonstrated that DNA-PKcs is a target for IL-1-converting enzyme (ICE)-like22 and CPP32-like apoptotic protease.23 We have previously reported that PS-341 induces caspase-3 cleavage in MM cells,4 so we next examined whether DNA-PKcs, ATM, or both are cleaved by caspase activation triggered by PS-341. As expected, PS-341 induces cleavage of DNA-PKcs (180-kDa protein) in a time- (Figure 4A, upper panel), and dose- (Figure 4A, lower panel) dependent fashion in MM.1S cells. PS-341-induced DNA-PKcs cleavage also occurs in RPMI 8226 (Figure 4B, upper panel) and U266 (Figure 4B, lower panel) MM cell lines. Although a constitutive DNA-PKcs cleaved form is present in patient MM cells, PS-341 also induces DNA-PKcs cleavage in these cells (Figure 4C). PS-341 similarly cleaves ATM in a time- (Figure 4D, upper panel), and dose- (Figure 4D, lower panel) dependent fashion in MM.1S cells. These results suggest that PS-341 may inhibit DNA repair by cleavage of DNA-PKcs, ATM, or both in MM cell lines and patient MM cells.
Mechanism by which PS-341 cleaves DNA-PKcs and ATM Having shown that PS-341 induces DNA-PKcs and ATM cleavage, we next examined the mechanism whereby PS-341 triggers the cleavage of these protein kinases. As in our prior study,4 PS-341 induces caspase-3 cleavage (Figure 5A, upper panel) and caspase-8 cleavage (Figure 5A, lower panel) in a time-dependent fashion. In contrast, there are no caspase-9 cleavage (data not shown) and no changes in phosphorylation of Bcl-2 or in protein expression of Bcl-2 and Bcl-XL (Figure 5B). To determine whether caspase-3 activation mediates DNA-PKcs or ATM cleavage induced by PS-341, we examined the effect of caspase inhibitors on DNA-PK and ATM cleavage (Figure 5C). As expected, pan-caspase inhibitor Z-VAD-FMK (4th lane) and caspase-8 inhibitor Z-IETD-FMK (3rd lane) completely abrogate DNA-PKcs and ATM cleavage induced by PS-341. These caspase inhibitors also abrogate PS-341-induced phosphorylation, but not protein expression, of p53 (Figure 5C). Because MDM2 is cleaved during apoptosis,24 we next examined whether PS-341 also cleaves MDM2. As seen in Figure 5D, MDM2 is completely cleaved after treatment with PS-341 for 10 hours. To define the role of ATM or ATR in the phosphorylation of p53 induced by PS-341 treatment, we used caffeine as an inhibitor of ATM25 and ATR.26 Caffeine inhibits PS-341-induced p53 phosphorylation, but not p53 protein expression, in MM.1S cells in a time- (Figure 5E, upper panel) and dose- (Figure 5E, lower panel) dependent fashion. These results suggest that PS-341 induces DNA-PKcs and ATM cleavage, phosphorylation of p53 and MDM2 cleavage through activation of caspase-3 by caspase-8.
UPP is a major proteolytic system that selectively removes
mutant, damaged, or misfolded proteins. It also regulates the
expression of proteins mediating cell-cycle progression
(p21Cip,1 p27Kip,1
cyclins), oncogenesis (p53, I Our previous study demonstrates that PS-341 induces apoptosis in MM cells with wild-type and mutant p53,4 consistent with previous reports that proteasome inhibitor-induced apoptosis occurs dependently5 or independently28 of p53 status. In this study, we hypothesized that DNA damage triggered by PS-341 treatment in MM cells is associated with the activation of DNA-PKcs, ATM/ATR, or both, and the activation of p53. We first report that PS-341 specifically induces the phosphorylation of p53 (Ser15). This induction of p53 phosphorylation is associated with increased p53 protein expression, as previously reported.29 PS-341 induces MDM2 protein and the association of p53 and MDM2 earlier than the phosphorylation of p53. Previous studies have demonstrated that the phosphorylation of p53 (Ser15) dissociates p53 from the p53/MDM2 complex; however, our results demonstrate p53 is still associated with MDM2 even after phosphorylation. Previous reports demonstrated that DNA damage induced the phosphorylation of p53 through the activation of DNA-PKcs20,30; therefore, our results strongly suggest that PS-341 induces DNA damage, activates DNA-PKcs, ATM/ATR, or both, and phosphorylates p53 (Ser15) in MM cell lines and primary patient MM cells. We have studied mechanisms whereby conventional and novel therapies trigger MM cell apoptosis. For example, Dex triggers caspase-9-mediated MM cell death,19 whereas immunomodulatory derivatives of thalidomide31 and TRAIL32 induce caspase 8-mediated apoptosis. Our recent gene microarray data of MM.1S cells treated with PS-341 demonstrates transcriptional triggering of apoptotic cascades, down-regulation of growth/survival kinases, up-regulation of UPP, and induction of stress kinases, including heat shock proteins (HSPs). JNK, one of these stress-response proteins, mediates apoptosis triggered by unfolded proteins.33 JNK inhibitor SP600125 blocks PS-341-induced cell death by the abrogation of caspase-3 cleavage but does not affect the phosphorylation of p53. These data suggest that the activation of JNK modulates PS-341-induced caspase activation and apoptosis. Previous reports demonstrate that JNK increases the phosphorylation of antiapoptotic proteins Bcl-2 and Bcl-x, thereby reducing their antiapoptic activity34,35; however, our data demonstrate that PS-341 does not alter the protein expression of Bcl-2 and Bcl-XL or the phosphorylation of Bcl-2. This result is consistent with our data that PS-341 does not induce the activation of caspase-9 but rather induces caspase-8 apoptotic signaling. DNA-PKcs is a phosphatidylinositol (PI) kinase that has a crucial role
in the repair of damaged DNA and the phosphorylation of selective
serine residues (Ser15) on p53,20,30 and it is a possible
target for an ICE-like protease22 or a CPP32-like apoptotic protease.23 Therefore, we sought to determine
whether the activation of caspases by PS-341 induces cleavage of
DNA-PKcs, ATM, or both. We demonstrated that PS-341 cleaves DNA-PKcs
and ATM in MM cell lines and primary patient MM cells. PS-341 activates caspase-3 through caspase-8 activation, whereas pan-caspase and caspase-8 inhibitors completely abrogate PS-341-induced
caspase-8/caspase-3 activation and DNA-PKcs and ATM cleavage. These
data suggest that the cleavage of DNA-PKcs and ATM triggered by PS-341
is dependent on caspase-8/caspase-3 signaling. Our results further
demonstrate that the inhibition of caspase activation also inhibits p53
phosphorylation, but not protein expression of p53, suggesting that the
phosphorylation of p53 is a secondary event following DNA damage
induced by caspase-3. Taken together, our findings indicate that PS-341
activates caspase-3 through caspase-8 activation, impairs DNA repair by
the cleavage of DNA-PKcs or ATM, and activates p53 through the
phosphorylation of p53 and the degradation of MDM2 (Figure
6). These effects all occur with PS-341
(20 nM) serum levels that are achieved in clinical trials; moreover,
PS-341 irreversibly binds to proteasomes and accumulates in target
cells. Further delineation of the molecular mechanisms mediating
antitumor activity of these agents will provide the framework for their
use, alone or coupled with other novel agents, to improve outcome.
These studies will also establish the molecular basis for the
development of more targeted, potent, and less toxic second-generation
proteasome inhibitors.
Submitted August 21, 2002; accepted September 17, 2002.
Prepublished online as Blood First Edition Paper, September 26, 2002; DOI 10.1182/blood-2002-08-2543.
Supported by National Institutes of Health grants PO-1 78378 and RO-1 CA 50947; the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.); the Multiple Myeloma Research Foundation (T.H., C.M., T.H., D.C., and N.M.); and the Myeloma Research Fund (K.C.A.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kenneth C. Anderson, Dana-Farber Cancer Institute, M557, 44 Binney St, Boston, MA 02115; e-mail: kenneth_anderson{at}dfci.harvard.edu.
1. Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001;8:739-758[CrossRef][Medline] [Order article via Infotrieve].
2.
Adams J, Palombella VJ, Sausville EA, et al.
Proteasome inhibitors: a novel class of potent and effective antitumor agents.
Cancer Res.
1999;59:2615-2622
3.
Sun J, Nam S, Lee CS, et al.
CEP1612, a dipeptidyl proteasome inhibitor, induces p21WAF1 and p27KIP1 expression and apoptosis and inhibits the growth of the human lung adenocarcinoma A-579 nude mice.
Cancer Res.
2001;61:1280-1284
4.
Hideshima T, Richardson P, Chauhan D, et al.
The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells.
Cancer Res.
2001;61:3071-3076
5.
Lopes UG, Erhardt P, Yao R, Cooper GM.
p53-dependent induction of apoptosis by proteasome inhibitors.
J Biol Chem.
1997;272:12893-12896 6. Herrmann JL, Briones FJ, Brisbay S, Logothetis CJ, McDonnell TJ. Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53. Oncogene. 1998;17:2889-2899[CrossRef][Medline] [Order article via Infotrieve].
7.
Frankel A, Man S, Elliott P, Adams J, Kerbel RS.
Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341.
Clin Cancer Res.
2000;6:3719-3728
8.
Orkowski RZ, Eswara JR, Lafond-Walker A, Grever MR, Orlowski M, Dang CV.
Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor.
Cancer Res.
1998;58:4342-4348
9.
Tan C, Waldmann TA.
Proteasome inhibitor PS-341, a potential therapeutic agent for adult T-cell leukemia.
Cancer Res.
2002;62:1083-1086
10.
Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J.
The proteasome inhibitor PS-341 in cancer therapy.
Clin Cancer Res.
1999;5:2638-2645
11.
Harbison MT, Bruns CJ, Bold RJ, et al.
Proteasome inhibitor PS-341 is effective as an antiangiogenic agent in the treatment of human pancreatic carcinoma via the inhibition of NF- 12. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer Statistics, 2000. CA Cancer J Clin. 2000;50:7-33[Abstract]. 13. Richardson PG, Berenson J, Irwin D, et al. Phase II trial of PS-341, a novel proteasome inhibitor, alone or in combination with dexamethasone, in patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy [abstract]. Blood. 2001;98:774.
14.
Hideshima T, Chauhan D, Shima Y, et al.
Thalidomide and its analogues overcome drug resistance of human multiple myeloma cells to conventional therapy.
Blood.
2000;96:2943-2950 15. Han Z, Boyle DL, Chang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108:73-81[CrossRef][Medline] [Order article via Infotrieve].
16.
Bennett BL, Sasaki DT, Murray BW, et al.
SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase.
Proc Natl Acad Sci U S A.
2001;98:13681-13686
17.
Hideshima T, Chauhan D, Richardson P, et al.
NF- 18. Chauhan D, Auclair D, Robinson EK, et al. Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. Oncogene. 2002;21:1346-1358[CrossRef][Medline] [Order article via Infotrieve]. 19. Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene. 2001;20:5991-6000[CrossRef][Medline] [Order article via Infotrieve].
20.
Tibbetts RS, Brumbaugh KM, Williams JM, et al.
A role for ATR in the DNA damaged-induced phosphorylation of p53.
Genes Dev.
1999;13:152-157
21.
Buschmann T, Potapova O, Bar-Shira A, et al.
Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.
Mol Cell Biol.
2001;21:2743-2754 22. Song Q, Lees-Miller SP, Kumar S, et al. DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease in apoptosis. EMBO J. 1996;15:3238-3246[Medline] [Order article via Infotrieve].
23.
Han Z, Malik N, Carter T, Reeves WH, Wyche JH, Hendrickson EA.
DNA-dependent protein kinase is a target for a CPP32-like apoptotic protease.
J Biol Chem.
1996;271:25035-25040
24.
Chen L, Marechal V, Moreau J, Levine AJ, Chen J.
Proteolytic cleavage of the mdm2 oncoprotein during apoptosis.
J Biol Chem.
1997;272:22966-22973
25.
Sarkaria JN, Busby EC, Tibbetts RS, et al.
Inhibition of ATM and ATR kinase activity by the radiosensitizing agent, caffeine.
Cancer Res.
1999;59:4375-4382 26. Hall-Jackson CA, Cross DA, Morrice N, Smythe C. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene. 1999;18:6707-6713[CrossRef][Medline] [Order article via Infotrieve].
27.
LeBlanc R, Catley LP, Hideshima T, et al.
Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.
Cancer Res.
2002;62:4996-5000 28. An WG, Hwang SG, Trepel JB, Blagosklonny MV. Proteasome inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia. 2000;14:1276-1283[CrossRef][Medline] [Order article via Infotrieve]. 29. Klibanov SA, O'Hagan HM, Ljungman M. Accumulation of soluble and nucleolar-associated p53 proteins following cellular stress. J Cell Sci. 2001;114:1867-1973[Abstract]. 30. Shieh SY, Ikeda M, Taya Y, Prives C. DNA damaged-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell. 1997;91:325-334[CrossRef][Medline] [Order article via Infotrieve].
31.
Mitsiades N, Mitsiades CS, Poulaki V, et al.
Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.
Blood.
2002;99:4525-4530
32.
Mitsiades CS, Treon SP, Mitsiades N, et al.
TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications.
Blood.
2001;98:795-804 33. Gabai VL, Meriin AB, Yaglom JA, Volloch VZ, Sherman MY. Role of Hsp70 in regulation of stress-kinase JNK: implications in apoptosis and aging. FEBS Lett. 1998;438:1-4[CrossRef][Medline] [Order article via Infotrieve].
34.
Srivastava RK, Sollott SJ, Khan L, Hansford R, Lakatta EG, Longo DL.
Bcl-2 and Bcl-X(L) block thapsigargin-induced nitric oxide generation, c-Jun NH(2)-terminal kinase activity, and apoptosis.
Mol Cell Biol.
1999;19:5659-5674 35. Kharbanda S, Saxena S, Yoshida K, et al. Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage. J Biol Chem. 1999;275:322-327.
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  S-W Lee, J-H Kim, Y-B Park, and S-K Lee Bortezomib attenuates murine collagen-induced arthritis Ann Rheum Dis, November 1, 2009; 68(11): 1761 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Badros, A. M. Burger, S. Philip, R. Niesvizky, S. S. Kolla, O. Goloubeva, C. Harris, J. Zwiebel, J. J. Wright, I. Espinoza-Delgado, et al. Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma Clin. Cancer Res., August 15, 2009; 15(16): 5250 - 5257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hideshima, H. Ikeda, D. Chauhan, Y. Okawa, N. Raje, K. Podar, C. Mitsiades, N. C. Munshi, P. G. Richardson, R. D. Carrasco, et al. Bortezomib induces canonical nuclear factor-{kappa}B activation in multiple myeloma cells Blood, July 30, 2009; 114(5): 1046 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-S. Eom, C.-K. Min, B.-S. Cho, S. Lee, J.-W. Lee, W.-S. Min, C.-C. Kim, M. Kim, and Y. Kim Retrospective Comparison of Bortezomib-containing Regimens with Vincristine-Doxorubicin-Dexamethasone (VAD) as Induction Treatment Prior to Autologous Stem Cell Transplantation for Multiple Myeloma Jpn. J. Clin. Oncol., July 1, 2009; 39(7): 449 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hoang, A. Benavides, Y. Shi, P. Frost, and A. Lichtenstein Effect of autophagy on multiple myeloma cell viability Mol. Cancer Ther., July 1, 2009; 8(7): 1974 - 1984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Roccaro, A. Sacco, B. Thompson, X. Leleu, A. K. Azab, F. Azab, J. Runnels, X. Jia, H. T. Ngo, M. R. Melhem, et al. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma Blood, June 25, 2009; 113(26): 6669 - 6680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, D. Chauhan, T. Kiziltepe, H. Ikeda, Y. Okawa, K. Podar, N. Raje, A. Protopopov, N. C. Munshi, P. G. Richardson, et al. Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications Blood, May 21, 2009; 113(21): 5228 - 5236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Butler, M. B. Moore, S. R. Presnell, H.-W. Chan, N. J. Chalupny, and C. T. Lutz Proteasome Regulation of ULBP1 Transcription J. Immunol., May 15, 2009; 182(10): 6600 - 6609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Troch, C. Jonak, L. Mullauer, A. Puspok, M. Formanek, W. Hauff, C. C. Zielinski, A. Chott, and M. Raderer A phase II study of bortezomib in patients with MALT lymphoma Haematologica, May 1, 2009; 94(5): 738 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Azab, J. M. Runnels, C. Pitsillides, A.-S. Moreau, F. Azab, X. Leleu, X. Jia, R. Wright, B. Ospina, A. L. Carlson, et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy Blood, April 30, 2009; 113(18): 4341 - 4351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Moore, E. L. Davenport, E. M. Smith, S. Muralikrishnan, A. S. Dunlop, B. A. Walker, D. Krige, A. H. Drummond, L. Hooftman, G. J. Morgan, et al. Aminopeptidase inhibition as a targeted treatment strategy in myeloma Mol. Cancer Ther., April 1, 2009; 8(4): 762 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. M. Yong, K. Keyvanfar, N. Hensel, R. Eniafe, B. N. Savani, M. Berg, A. Lundqvist, S. Adams, E. M. Sloand, J. M. Goldman, et al. Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib Blood, January 22, 2009; 113(4): 875 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Dawson, S. S. Opat, Y. Taouk, M. Donovan, M. Zammit, K. Monaghan, N. Horvath, A. W. Roberts, H. M. Prince, M. Hertzberg, et al. Clinical and Immunohistochemical Features Associated with a Response to Bortezomib in Patients with Multiple Myeloma Clin. Cancer Res., January 15, 2009; 15(2): 714 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Koldehoff, D. W. Beelen, and A. H. Elmaagacli Small-molecule inhibition of proteasome and silencing by vascular endothelial cell growth factor-specific siRNA induce additive antitumor activity in multiple myeloma J. Leukoc. Biol., August 1, 2008; 84(2): 561 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Markovina, N. S. Callander, S. L. O'Connor, J. Kim, J. E. Werndli, M. Raschko, C. P. Leith, B. S. Kahl, K. Kim, and S. Miyamoto Bortezomib-Resistant Nuclear Factor-{kappa}B Activity in Multiple Myeloma Cells Mol. Cancer Res., August 1, 2008; 6(8): 1356 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Poff, C. T. Allen, B. Traughber, A. Colunga, J. Xie, Z. Chen, B. J. Wood, C. Van Waes, K. C. P. Li, and V. Frenkel Pulsed High-Intensity Focused Ultrasound Enhances Apoptosis and Growth Inhibition of Squamous Cell Carcinoma Xenografts with Proteasome Inhibitor Bortezomib Radiology, August 1, 2008; 248(2): 485 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Carew, S. T. Nawrocki, V. K. Reddy, D. Bush, J. E. Rehg, A. Goodwin, J. A. Houghton, R. A. Casero Jr, L. J. Marton, and J. L. Cleveland The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib Cancer Res., June 15, 2008; 68(12): 4783 - 4790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Roccaro, X. Leleu, A. Sacco, X. Jia, M. Melhem, A.-S. Moreau, H. T. Ngo, J. Runnels, A. Azab, F. Azab, et al. Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia Blood, May 1, 2008; 111(9): 4752 - 4763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Suvannasankha, C. D. Crean, R. Shanmugam, S. S. Farag, R. Abonour, H. S. Boswell, and H. Nakshatri Antimyeloma Effects of a Sesquiterpene Lactone Parthenolide Clin. Cancer Res., March 15, 2008; 14(6): 1814 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Roccaro, X. Leleu, A. Sacco, A.-S. Moreau, E. Hatjiharissi, X. Jia, L. Xu, B. Ciccarelli, C. J. Patterson, H. T. Ngo, et al. Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenstrom's Macroglobulinemia Clin. Cancer Res., March 15, 2008; 14(6): 1849 - 1858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Shin, Y.-S. Chun, D. S. Lee, L. E. Huang, and J.-W. Park Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1 Blood, March 15, 2008; 111(6): 3131 - 3136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vales-Gomez, S. E. Chisholm, R. L. Cassady-Cain, P. Roda-Navarro, and H. T. Reyburn Selective Induction of Expression of a Ligand for the NKG2D Receptor by Proteasome Inhibitors Cancer Res., March 1, 2008; 68(5): 1546 - 1554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Colado, S. Alvarez-Fernandez, P. Maiso, J. Martin-Sanchez, M. B. Vidriales, M. Garayoa, E. M. Ocio, J. C. Montero, A. Pandiella, and J. F. San Miguel The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype Haematologica, January 1, 2008; 93(1): 57 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-K. Min, M.-J. Lee, K.-S. Eom, S. Lee, J.-W. Lee, W.-S. Min, C.-C. Kim, M. Kim, J. Lim, Y. Kim, et al. Bortezomib in Combination with Conventional Chemotherapeutic Agents for Multiple Myeloma Compared with Bortezomib Alone Jpn. J. Clin. Oncol., December 21, 2007; (2007) hym126v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Kuhn, Q. Chen, P. M. Voorhees, J. S. Strader, K. D. Shenk, C. M. Sun, S. D. Demo, M. K. Bennett, F. W. B. van Leeuwen, A. A. Chanan-Khan, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma Blood, November 1, 2007; 110(9): 3281 - 3290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Davenport, H. E. Moore, A. S. Dunlop, S. Y. Sharp, P. Workman, G. J. Morgan, and F. E. Davies Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells Blood, October 1, 2007; 110(7): 2641 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Z. Orlowski, A. Nagler, P. Sonneveld, J. Blade, R. Hajek, A. Spencer, J. San Miguel, T. Robak, A. Dmoszynska, N. Horvath, et al. Randomized Phase III Study of Pegylated Liposomal Doxorubicin Plus Bortezomib Compared With Bortezomib Alone in Relapsed or Refractory Multiple Myeloma: Combination Therapy Improves Time to Progression J. Clin. Oncol., September 1, 2007; 25(25): 3892 - 3901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kiziltepe, T. Hideshima, K. Ishitsuka, E. M. Ocio, N. Raje, L. Catley, C.-Q. Li, L. J. Trudel, H. Yasui, S. Vallet, et al. JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells Blood, July 15, 2007; 110(2): 709 - 718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kiziltepe, T. Hideshima, L. Catley, N. Raje, H. Yasui, N. Shiraishi, Y. Okawa, H. Ikeda, S. Vallet, S. Pozzi, et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells Mol. Cancer Ther., June 1, 2007; 6(6): 1718 - 1727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Colla, F. Zhan, W. Xiong, X. Wu, H. Xu, O. Stephens, S. Yaccoby, J. Epstein, B. Barlogie, and J. D. Shaughnessy Jr The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells Blood, May 15, 2007; 109(10): 4470 - 4477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Strauss, K. Higginbottom, S. Juliger, L. Maharaj, P. Allen, D. Schenkein, T. A. Lister, and S. P. Joel The Proteasome Inhibitor Bortezomib Acts Independently of p53 and Induces Cell Death via Apoptosis and Mitotic Catastrophe in B-Cell Lymphoma Cell Lines Cancer Res., March 15, 2007; 67(6): 2783 - 2790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakob, K. Egerer, P. Liebisch, S. Turkmen, I. Zavrski, U. Kuckelkorn, U. Heider, M. Kaiser, C. Fleissner, J. Sterz, et al. Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma Blood, March 1, 2007; 109(5): 2100 - 2105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Podar, M. S. Raab, G. Tonon, M. Sattler, D. Barila, J. Zhang, Y.-T. Tai, H. Yasui, N. Raje, R. A. DePinho, et al. Up-Regulation of c-Jun Inhibits Proliferation and Induces Apoptosis via Caspase-Triggered c-Abl Cleavage in Human Multiple Myeloma Cancer Res., February 15, 2007; 67(4): 1680 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Richardson, T. Hideshima, and K. C. Anderson Plasma cell dyscrasias ASH Self-Assessment Program, January 1, 2007; 2007(1): 298 - 327. [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Fribley, B. Evenchik, Q. Zeng, B. K. Park, J. Y. Guan, H. Zhang, T. J. Hale, M. S. Soengas, R. J. Kaufman, and C.-Y. Wang Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa J. Biol. Chem., October 20, 2006; 281(42): 31440 - 31447. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lundqvist, S. I. Abrams, D. S. Schrump, G. Alvarez, D. Suffredini, M. Berg, and R. Childs Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res., July 15, 2006; 66(14): 7317 - 7325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ruiz, Y. Krupnik, M. Keating, J. Chandra, M. Palladino, and D. McConkey The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. Mol. Cancer Ther., July 1, 2006; 5(7): 1836 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, L. Catley, H. Yasui, K. Ishitsuka, N. Raje, C. Mitsiades, K. Podar, N. C. Munshi, D. Chauhan, P. G. Richardson, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells Blood, May 15, 2006; 107(10): 4053 - 4062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Olivier, P. Close, E. Castermans, L. de Leval, S. Tabruyn, A. Chariot, M. Malaise, M.-P. Merville, V. Bours, and N. Franchimont Raloxifene-Induced Myeloma Cell Apoptosis: A Study of Nuclear Factor-{kappa}B Inhibition and Gene Expression Signature Mol. Pharmacol., May 1, 2006; 69(5): 1615 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Nawrocki, J. S. Carew, M. S. Pino, R. A. Highshaw, R. H.I. Andtbacka, K. Dunner Jr., A. Pal, W. G. Bornmann, P. J. Chiao, P. Huang, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res., April 1, 2006; 66(7): 3773 - 3781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sors, F. Jean-Louis, C. Pellet, L. Laroche, L. Dubertret, G. Courtois, H. Bachelez, and L. Michel Down-regulating constitutive activation of the NF-{kappa}B canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis Blood, March 15, 2006; 107(6): 2354 - 2363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T. Efuet and K. Keyomarsi Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome Cancer Res., January 15, 2006; 66(2): 1040 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fernandez, T. P. Miller, C. Denoyelle, J. A. Esteban, W.-H. Tang, A. L. Bengston, and M. S. Soengas Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib: IMPACT ON TUMOR CELL DEATH J. Biol. Chem., January 13, 2006; 281(2): 1107 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. San Miguel, J. Blade, M. Boccadoro, J. Cavenagh, A. Glasmacher, S. Jagannath, S. Lonial, R. Z. Orlowski, P. Sonneveld, and H. Ludwig A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma Oncologist, January 1, 2006; 11(1): 51 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Dasmahapatra, M. Rahmani, P. Dent, and S. Grant The tyrphostin adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells through a reactive oxygen species (ROS)-dependent mechanism Blood, January 1, 2006; 107(1): 232 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Perez-Galan, G. Roue, N. Villamor, E. Montserrat, E. Campo, and D. Colomer The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status Blood, January 1, 2006; 107(1): 257 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, J. E. Bradner, D. Chauhan, and K. C. Anderson Intracellular Protein Degradation and Its Therapeutic Implications Clin. Cancer Res., December 15, 2005; 11(24): 8530 - 8533. [Full Text] [PDF]
|
|
|
|
|
|
E. David, S.-Y. Sun, E. K. Waller, J. Chen, F. R. Khuri, and S. Lonial The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT Blood, December 15, 2005; 106(13): 4322 - 4329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Zhu, J. Ramos, K. Kampa, S. Adimoolam, M. Sirisawad, Z. Yu, D. Chen, L. Naumovski, and C. D. Lopez Control of ASPP2/53BP2L Protein Levels by Proteasomal Degradation Modulates p53 Apoptotic Function J. Biol. Chem., October 14, 2005; 280(41): 34473 - 34480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, H. Yan, P. Frost, J. Gera, and A. Lichtenstein Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade Mol. Cancer Ther., October 1, 2005; 4(10): 1533 - 1540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hachem and R. B. Gartenhaus Oncogenes as molecular targets in lymphoma Blood, September 15, 2005; 106(6): 1911 - 1923. [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Saunders Overview of drug therapy for multiple myeloma Journal of Oncology Pharmacy Practice, September 1, 2005; 11(3): 83 - 100. [Abstract] [PDF]
|
|
|
|
|
|
K. Ishitsuka, T. Hideshima, M. Hamasaki, N. Raje, S. Kumar, H. Hideshima, N. Shiraishi, H. Yasui, A. M. Roccaro, P. Richardson, et al. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis Blood, September 1, 2005; 106(5): 1794 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Z. Qin, J. Ziffra, L. Stennett, B. Bodner, B. K. Bonish, V. Chaturvedi, F. Bennett, P. M. Pollock, J. M. Trent, M. J.C. Hendrix, et al. Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells Cancer Res., July 15, 2005; 65(14): 6282 - 6293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. G. Richardson, P. Sonneveld, M. W. Schuster, D. Irwin, E. A. Stadtmauer, T. Facon, J.-L. Harousseau, D. Ben-Yehuda, S. Lonial, H. Goldschmidt, et al. Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma N. Engl. J. Med., June 16, 2005; 352(24): 2487 - 2498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Zhu, E. Gerbino, D. M. Beaupre, P. A. Mackley, C. Muro-Cacho, C. Beam, A. D. Hamilton, M. G. Lichtenheld, W. G. Kerr, W. Dalton, et al. Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells Blood, June 15, 2005; 105(12): 4759 - 4766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hideshima, J. E. Bradner, J. Wong, D. Chauhan, P. Richardson, S. L. Schreiber, and K. C. Anderson Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma PNAS, June 14, 2005; 102(24): 8567 - 8572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Pekol, J. S. Daniels, J. Labutti, I. Parsons, D. Nix, E. Baronas, F. Hsieh, L.-S. Gan, and G. Miwa HUMAN METABOLISM OF THE PROTEASOME INHIBITOR BORTEZOMIB: IDENTIFICATION OF CIRCULATING METABOLITES Drug Metab. Dispos., June 1, 2005; 33(6): 771 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hamasaki, T. Hideshima, P. Tassone, P. Neri, K. Ishitsuka, H. Yasui, N. Shiraishi, N. Raje, S. Kumar, D. H. Picker, et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo Blood, June 1, 2005; 105(11): 4470 - 4476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Landowski, C. J. Megli, K. D. Nullmeyer, R. M. Lynch, and R. T. Dorr Mitochondrial-Mediated Disregulation of Ca2+ Is a Critical Determinant of Velcade (PS-341/Bortezomib) Cytotoxicity in Myeloma Cell Lines Cancer Res., May 1, 2005; 65(9): 3828 - 3836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Z. Orlowski, P. M. Voorhees, R. A. Garcia, M. D. Hall, F. J. Kudrik, T. Allred, A. R. Johri, P. E. Jones, A. Ivanova, H. W. Van Deventer, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies Blood, April 15, 2005; 105(8): 3058 - 3065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Ma, K.-i. Otsuyama, S. Liu, S. Abroun, H. Ishikawa, N. Tsuyama, M. Obata, F.-J. Li, X. Zheng, Y. Maki, et al. Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells Blood, April 15, 2005; 105(8): 3312 - 3318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Chauhan, T. Hideshima, C. Mitsiades, P. Richardson, and K. C. Anderson Proteasome inhibitor therapy in multiple myeloma Mol. Cancer Ther., April 1, 2005; 4(4): 686 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Storling, N. Allaman-Pillet, A. E. Karlsen, N. Billestrup, C. Bonny, and T. Mandrup-Poulsen Antitumorigenic Effect of Proteasome Inhibitors on Insulinoma Cells Endocrinology, April 1, 2005; 146(4): 1718 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nikrad, T. Johnson, H. Puthalalath, L. Coultas, J. Adams, and A. S. Kraft The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim Mol. Cancer Ther., March 1, 2005; 4(3): 443 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Piva, P. Gianferretti, A. Ciucci, R. Taulli, G. Belardo, and M. G. Santoro 15-Deoxy-{Delta}12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-{kappa}B activity and down-regulation of antiapoptotic proteins Blood, February 15, 2005; 105(4): 1750 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Goy, A. Younes, P. McLaughlin, B. Pro, J. E. Romaguera, F. Hagemeister, L. Fayad, N. H. Dang, F. Samaniego, M. Wang, et al. Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma J. Clin. Oncol., February 1, 2005; 23(4): 667 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Rajkumar, P. G. Richardson, T. Hideshima, and K. C. Anderson Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer J. Clin. Oncol., January 20, 2005; 23(3): 630 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Z. Orlowski The Ubiquitin Proteasome Pathway from Bench to Bedside Hematology, January 1, 2005; 2005(1): 220 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Small, Y. Y. Shi, N. A. Edmund, S. Somasundaram, D. T. Moore, and R. Z. Orlowski Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role Mol. Pharmacol., December 1, 2004; 66(6): 1478 - 1490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Fribley, Q. Zeng, and C.-Y. Wang Proteasome Inhibitor PS-341 Induces Apoptosis through Induction of Endoplasmic Reticulum Stress-Reactive Oxygen Species in Head and Neck Squamous Cell Carcinoma Cells Mol. Cell. Biol., November 15, 2004; 24(22): 9695 - 9704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kyle and S. V. Rajkumar Multiple Myeloma N. Engl. J. Med., October 28, 2004; 351(18): 1860 - 1873. [Full Text] [PDF]
|
|
|
|
|
|
D. Chauhan, G. Li, K. Podar, T. Hideshima, C. Mitsiades, R. Schlossman, N. Munshi, P. Richardson, F. E. Cotter, and K. C. Anderson Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells Blood, October 15, 2004; 104(8): 2458 - 2466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu, M. Farah, J. M. Webster, and R. J.H. Wojcikiewicz Bortezomib rapidly suppresses ubiquitin thiolesterification to ubiquitin-conjugating enzymes and inhibits ubiquitination of histones and type I inositol 1,4,5-trisphosphate receptor Mol. Cancer Ther., October 1, 2004; 3(10): 1263 - 1269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. An, Y. Sun, M. Fisher, and M. B. Rettig Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-{kappa}B dependent Mol. Cancer Ther., June 1, 2004; 3(6): 727 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-Y. Pei, Y. Dai, and S. Grant Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitors Clin. Cancer Res., June 1, 2004; 10(11): 3839 - 3852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bonvini, H. D. Rosa, N. Vignes, and A. Rosolen Ubiquitination and Proteasomal Degradation of Nucleophosmin-Anaplastic Lymphoma Kinase Induced by 17-Allylamino-Demethoxygeldanamycin: Role of the Co-Chaperone Carboxyl Heat Shock Protein 70-Interacting Protein Cancer Res., May 1, 2004; 64(9): 3256 - 3264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Dai, X.-Y. Pei, M. Rahmani, D. H. Conrad, P. Dent, and S. Grant Interruption of the NF-{kappa}B pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells Blood, April 1, 2004; 103(7): 2761 - 2770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. C. Anderson Proteasome inhibitor therapy of multiple myeloma. AACR Meeting Abstracts, March 1, 2004; 2004(1): 1316 - 1316. [Abstract]
|
|
|
|
|
|
T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al. Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma Cancer Res., December 1, 2003; 63(23): 8428 - 8436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Williams and D. J. McConkey The Proteasome Inhibitor Bortezomib Stabilizes a Novel Active Form of p53 in Human LNCaP-Pro5 Prostate Cancer Cells Cancer Res., November 1, 2003; 63(21): 7338 - 7344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-H. Lee, N. N. Iwakoshi, K. C. Anderson, and L. H. Glimcher Inaugural Article: Proteasome inhibitors disrupt the unfolded protein response in myeloma cells PNAS, August 19, 2003; 100(17): 9946 - 9951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Richardson, B. Barlogie, J. Berenson, S. Singhal, S. Jagannath, D. Irwin, S. V. Rajkumar, G. Srkalovic, M. Alsina, R. Alexanian, et al. A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma N. Engl. J. Med., June 26, 2003; 348(26): 2609 - 2617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shaughnessy, J. Jacobson, J. Sawyer, J. McCoy, A. Fassas, F. Zhan, K. Bumm, J. Epstein, E. Anaissie, S. Jagannath, et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression Blood, May 15, 2003; 101(10): 3849 - 3856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mitsiades, C. S. Mitsiades, P. G. Richardson, V. Poulaki, Y.-T. Tai, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications Blood, March 15, 2003; 101(6): 2377 - 2380. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
with 5-fluorouracil, cisplatin, paclitaxel (Taxol), and doxorubicin hydrochloride (Adriamycin)
20°C, and used at 5 to 80 nM in the presence of 5% FBS. JNK inhibitor 600215
),
HSP40 (
), HSP70 (
), HSP90 (
), and HSP110 (
) mRNA in MM.1S
cells treated with PS-341.
) or presence of 5 µM
(
) and 10 µM (
B), and apoptosis (Bcl, cIAP, XIAP,
Bax).